Essential tremor (ET) is a common movement disorder. Nearly 1% of population and 4–5% in persons ≥ 65 years old suffered from this disease (Shanker, 2019), and the prevalence of ET grows in an exponential manner with aging populations (Louis, 2019). Although pathophysiological mechanisms of ET remain unclear, cerebellar oscillator hypothesis and cerebellar decoupling hypothesis have been raised (Erro et al., 2022). One frequently mentioned hypothesis suggests that genetic, epigenetic and environmental factors work together to cause lesions in the inferior olive nucleus and cerebellum, which lead to abnormal function of circuitry involving the cerebello–thalamo–cortical pathway, and ultimately result in tremor with or without additional soft neurological signs of uncertain clinical significance (Shanker, 2019).
Over 50% of ET individuals have family history, suggesting genetic factors play a major role in ET pathogenesis. To date, at least 14 loci and 11 ET pathogenic genes have been described and various risk or protective genetic factors have been discovered. Through linkage analysis, ETM1 (Gulcher et al., 1997), ETM2 (Higgins et al., 1997) and ETM3 (Shatunov et al., 2006) were identified. Whole exome sequencing (WES) and whole genome-wide scan (WGS) discovered several candidate genes in ET families, including FUS (Merner et al., 2012), TENM4 (Hor et al., 2015), HTRA2 (Unal Gulsuner et al., 2014), SCN4A (Bergareche et al., 2015), SORT1 (Sánchez et al., 2015), SCN11A (Leng et al., 2017), NOS3, HAPLN4, USP46 (Liu et al., 2016), CACNA1G, SLIT3, KARS, KIF5A (Odgerel et al., 2019), CCDC183, MMP10 and GPR151 (Diez-Fairen et al., 2021). ET is also associated with abnormal GGC repeat expansion in the 5’ region of NOTCH2NLC gene with a detection rate of 1.32–5.58% in Chinese's ET pedigrees (Sun et al., 2020; Yan et al., 2020) but much lower in Caucasian populations (Liao et al., 2020a; Yau et al., 2021). In addition, several genome-wide association studies (GWAS) have been conducted for ET (Liao et al., 2022; Müller et al., 2016; Stefansson et al., 2009; Thier et al., 2012). To date, more than 20 possibly related single-nucleotide polymorphisms (SNPs) have been reported in previous studies. The Asian population is the largest worldwide and thus makes up a significant fraction of patients with ET globally. Studies have demonstrated both similarities and differences in genetic factors underlying ET in Asian and European individuals, such as the protective role of C allele of rs10937625 in STK32B and risk factor rs7903491 in CTNNA3 (Müller et al., 2016; Xiao et al., 2017; Zhang et al., 2017). However, only part of SNPs reported have been tested in Chinese Han population (Chen et al., 2019; Zhang et al., 2017; Zuo et al., 2010), and due to the limited sample size and high clinical heterogeneity, no definite relationships have been established between the SNPs and ET etiology. Further studies are needed to confirm contributions of these SNPs to the pathogenesis of ET and explore any underlying mechanisms.
To identify SNPs that modulate the risk of ET in the Chinese Han population, we designed a case-control study to evaluate the association between 27 SNPs in 19 genes and ET in an Eastern Chinese patient cohort.